CD97 is a member of the adhesion family of G-protein coupled receptors (GPCR) and is normally expressed at high levels constitutively on myeloid cells. In some epithelial cancers CD97 levels have been positively correlated with dedifferentiation and malignant grade. . The primary structure of CD97 suggests a G-protein coupled receptor (GPCR), which utilizes an adhesion class of ligand. We have determined that CD97 signals through Galpha12 and 13. In order to address the function of CD97 relative to cancer biology, we have used several approaches that assess invasiveness and tumorigenicity. CD97 is expressed in thyroid, colon, and prostate cancers but not in the normal epithelial counterparts. Reducing CD97 expression in prostate cancer cell lines inhibits their migration and invasion in vitro. CD97-dependent migration has been analyzed in prostate cancer cells with respect to chemoattractant ligands and downstream signaling pathways. These data suggest that CD97-dependent migration results from the interaction of CD97 with other chemoattractant receptors. We have recently demonstrated the physical and functional interaction of CD97 with the LPA receptor. Although CD97 is absent in normal thyroid epithelial cells, it has been demonstrated that CD97 expression increases during thyroid cancer dedifferentiation and progression to anaplasia. However, there is no previous evidence of a direct function of CD97 in cancer progression. To address the question of a potential role of CD97 in thyroid cancer development and progression, we generated a CD97 transgenic mouse model constitutively expressing human CD97 in the follicular epithelial cells of the thyroid and crossed this CD97 transgenic mouse with the TRPV/PV mouse. The TRbetaPV/PV mouse spontaneously develops follicular thyroid adenoma with pathological progression to carcinoma, which has similarities to human cancer. Studies have indicated that the TRbetaPV/PV mouse is a valid preclinical mouse model to identify potential molecular targets for the treatment of thyroid cancer. We showed that constitutive expression of CD97 in the follicular epithelium can promote thyroid cancer progression. TRbetaPV/PV mice expressing CD97 exhibited increased occurrence of vascular invasion, a correlate of progression to carcinoma, and lung metastasis with a more aggressive histology than the TRbetaPV/PV mice without CD97. Furthermore, we showed that the expression of CD97 in TRbetaPV/PV mice increased ERK phosphorylation suggesting that CD97 may drive cancer progression by activating this pathway to increase tumor cell migration and invasion. In addition, constitutive CD97 expression resulted in higher Ki67 indicating that CD97 also plays a role in increasing proliferation. Furthermore, primary cultured thyroid organoids from TRbetaPV/PV mice expressing CD97 demonstrated enhanced ERK phosphorylation following LPA stimulation, suggesting that an LPA/RHO/ERK axis contributes to the mechanism of CD97 dependent progression. The present study provides in vivo evidence for a direct role of CD97 in thyroid cancer progression, suggesting that this G-protein coupled receptor may be an important target for chemotherapeutic intervention of thyroid cancer.